Abstract 2528: New ovarian cancer approach based on sensitizing the MDM2 inhibitor by an exportin-1 inhibitor
Authors: Amal Alzahrani, Umamaheswari Natarajan, Samia Alsubhi, Ahmed Alsarrani, Appu Rathinavelu
Journal: Cancer Research (2023)

Abstract Objective: The study is to investigate the efficacy of MDM2 inhibitor RG-7388 in combination with Selinexor on ovarian cancer cells. Background: According to the Center for Disease Control (CDC), in the United States of America, ovarian cancer is considered the second most common gynecologic cancer, after breast cancer, with a mortality rate higher than any other cancer of the female reproductive system. Researchers are constantly investigating molecular alterations in ovarian cancer to develop targeted therapies, particularly those affecting cell death and cell cycle progression. The majority of ovarian cancer cells exhibit mutations or inactivation of p53, contributing to both metastatic progression and chemoresistance. In this regard, Exportin-1 (XPO1), which is a protein that regulates the nuclear export of several cancer suppressor proteins including p53, seems to be involved in ovarian cancer growth and progression. Furthermore, there is an association between overexpression of XPO1 and resistance to chemotherapy, which is also associated with a poor prognosis for ovarian cancer patients. Our study aimed to develop new treatment strategies for ovarian cancer by combining RG-7388 with Selinexor, which is an inhibitor of the nuclear export mechanism. Methods: For the cell death analysis, MTT assay was conducted after treating A2780 cells with RG-7388, Selinexor, and a combination of them at different doses for 24h. Western Blotting analysis was conducted to assess the protein expression levels of MDM2, p53, phospho-p53, and p21. Fluorescence imaging with DEVD-amc fluorogenic substrates was applied to determine the apoptotic effect of RG-7388 and Selinexor. Results: A combination of RG-7388 (1µM) and Selinexor (1µM) was able to reduce 50 percent of cell viability after 24 h compared to individual treatments of (2µM) RG-7388 and (2µM) Selinexor. Moreover, the combination of RG-7388 and Selinexor revealed significant upregulation of MDM2, p53, phospho-p53, and p21 in the whole lysate, cytosolic, and nuclear fraction of the A2780 cells. Finally, the ovarian cancer cells treated with the combination of the inhibitors produced elevated fluorescence levels compared to individual treatments, indicating activation of caspases in apoptosis progression. Conclusion: Our results confirmed that the combination treatment with RG-7388 (1M) and Selinexor (1M), which has never been investigated before for treating ovarian cancer cells, reduced the cell viability, upregulated apoptotic proteins, and induced cell death through activation of caspase-mediated apoptotic mechanisms. Grants: The Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida, provided the funds for this study. Citation Format: Amal Alzahrani, Umamaheswari Natarajan, Samia Alsubhi, Ahmed Alsarrani, Appu Rathinavelu. New ovarian cancer approach based on sensitizing the MDM2 inhibitor by an exportin-1 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2528.